4-Amino-6, 7-dimethoxy-2-(4-heteroaryl-piperazino) quinazoline _antihypertensives

ABSTRACT

2,4-Diaminoquinazoline compounds of the formula ##STR1## or a pharmaceutically acceptable salt thereof wherein R is a pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl group linked to the piperazine ring by one of its carbon atoms, and optionally substituted by hydroxy, halogen, alkyl, aralkyl, alkoxy, aralkoxy,alkylthio, aryl, aryloxy and certain amino groups; their use as an antihypertensive agent and pharmaceutical compositions containing them.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 333,672 filedDec. 23, 1981. Now U.S. Pat. No. 4,435,401, issued Mar. 6, 1984.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to therapeutic agents which are novel derivativesof 4-amino-6,7-dimethoxy-2-piperazinoquinazoline, their use asregulators of the cardiovascular system, particularly in the treatmentof hypertension and pharmaceutical compositions containing them.

2. Description of the Prior Art

U.S. Pat. No. 3,511,836 discloses 4-amino-6,7-dimethoxyquinazolines andU.S. Pat. No. 3,669,968 discloses related 6,7,8-trimethoxyquinazolinesof the formula ##STR2## useful as antihypertensive agents, wherein R^(a)is hydrogen or methoxy, respectively, and R^(b) is inter alia, phenyl,benzyl, benzoyl, furoyl, thenoyl and pyridinecarbonyl. One of thesecompounds,2-[4-(2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline, is aclinically useful antihypertensive agent marketed under the generic name"prazosin".

U.S. Pat. No. 3,517,005 discloses antihypertensives including those ofthe formula ##STR3## where R^(c) is hydrogen or alkyl and R^(d) is interalia an aryl hydrocarbon moiety.

European Patent Application No. 22481 published Jan. 21, 1981 disclosesantihypertensive agents of the formula ##STR4## where n is 3, 4 or 5 andR^(e) is, inter alia, a nitrogen-containing heterocyclic group, e.g.,pyridyl, pyrimidinyl, quinolyl or quinazolyl; and Y is e.g. asubstituted or unsubstituted amino group.

SUMMARY OF THE INVENTION

The present invention discloses new 4-amino-6,7-dimethoxyquinazolines ofthe formula ##STR5## or a pharmaceutically acceptable acid addition saltthereof, wherein R is a nitrogen heterocyclic group linked to thepiperazine ring by one of its carbon atoms, said heterocyclic groupbeing a member selected from the group consisting of ##STR6## where R¹is hydrogen and R² is 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl,or R¹ and R² are each a member selected from the group consisting ofhydrogen, hydroxy, F, Cl, Br, I, (alk)R³, O(alk) R³, S(alk) R³, NR⁴ R⁵,C₆ H₄ R⁶ and OC₆ H₄ R⁶ and (alk) is (C₁ -C₄) alkylene, R³ is hydrogen orC₆ H₄ R⁶, when taken separately, R⁴ is hydrogen or (C₁ -C₄) alkyl and R⁵is hydrogen, phenyl, (alk)R₃ or (C₃ -C₇) cycloalkyl, or taken togetherwith the nitrogen atom to which they are attached, R⁴ and R⁵ form a1-pyrrolidinyl, piperidino, 4-methylpiperazino, morpholino, orthiomorpholino group, and R⁶ is hydrogen, F, Cl, Br, I, (C₁ -C₄) alkylor (C₁ -C₄) alkoxy.

Hydroxy substituted heterocyclic groups, R, may occur in tautomericform. Such tautomers are within the scope of the invention.

Particularly preferred values of substituent R are the optionallysubstituted 2-pyrimidinyl, 4-pyrimidinyl, 1,3,5-triazin-2-yl,3-pyridazinyl and 2-pyrazinyl moieties below ##STR7##

More particularly preferred compounds of the invention are those where Rhas one of the above values and:

a. one of R¹ and R² is hydrogen and the other is a member selected fromthe group consisting of hydroxy, Cl, Br, phenyl, phenoxy, (alk)R³,O(alk)R³, S(alk)R³, NR⁴ R⁵ and6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl, where R³ is hydrogen,R⁴ is hydrogen or (C₁ -C₄) alkyl and R⁵ is hydrogen, phenyl, (C₅ -C₆)cycloalkyl or (alk)R³ where R³ is hydrogen, or R⁴ and R⁵ taken togetherwith the nitrogen atom to which they are attached form a morpholinogroup; or

b. R¹ and R² are the same and are each hydrogen, phenoxy, O(alk)R³ orNHR⁵ where R⁵ is hydrogen or (alk)R³, and R³ is hydrogen.

Even more particularly preferred are those compounds of formula (I)wherein R has one of the values below. ##STR8##

Pharmaceutically acceptable acid addition salts of the compounds of theinvention are those formed from acids which form non-toxic acid additionsalts containing pharmaceutically acceptable anions, such as thehydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acidphosphate, acetate, maleate, fumarate, succinate, lactate, tartrate,citrate, glucconate, saccharate, mesylate and p-toluenesulphonate salts.

The compounds of formula (I) are valuable antihypertensive agents havingsignificant advantages over the prior art.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the formula (I) can be prepared by reacting aquinazoline of the formula: ##STR9## where Q is a facile leaving group,e.g., Cl, Br, C₁ -C₄ alkoxy or C₁ -C₄ alkylthio; with a piperazine ofthe formula: ##STR10## where R is as previously defined. A particularlypreferred value for Q is Cl.

In a typical procedure the reactants are heated together, e.g., at70°-150° C., preferably under reflux, in a suitable solvent, e.g.,r-butanol, for up to about 25 hours, the exact period of time of coursedepending on the nature of the reactants and the temperature employed,as will be known to those skilled in the art. The product can then beisolated and purified by conventional procedures.

If compound (III) is added in the form of an acid addition salt, then atertiary amine base such as triethylamine is preferably added to thereaction mixture to release the free base of formula (III).

The starting materials of formula (III) are either known compounds ormay be prepared by methods analogous to those of the prior art, many ofsuch methods being illustrated in Preparations A to I. The startingquinazoline compounds of formula (II) are well known in the art; seee.g., U.S. Pat. No. 3,511,836.

The compounds of the formula (I) can also be prepared by reacting a2-piperazinoquinazoline of the formula: ##STR11## with a heterocycle ofthe formula:

    R--Q                                                       (V)

where

R and Q are as previously defined and

Q is preferably Cl.

The reaction may be carried out in a similar manner to the previousmethod. Similarly, the product may be isolated and purified byconventional procedure. The starting materials of the formula (V) areeither known compounds of may be prepared by methods analogous to thoseof the prior art. The starting 2-piperazinoquinazoline (IV) is provided,for example, in U.S. Pat. No. 3,511,836.

Some of the compounds of the formula (I) can be prepared from othercompounds of the formula (I). For example, compounds of the formula (I)in which R contains NR⁴ R⁵, where R⁴ and R⁵ are as defined for formula(I), can be prepared by reacting the corresponding compound in which Ris a halogen substituted moiety with the appropriate amine of theformula R⁴ R⁵ NH. Generally, fairly vigorous reaction conditions arenecessary, e.g., heating the reactants in a suitable solvent, e.g.,n-butanol, at up to 180° C. in a bomb, for up to about 48 hours. Apreferred halogen substituent is chloro.

Requisite starting compounds R Q, as defined above, are either knowncompounds or are prepared by analogous methods well known to those ofskill in the art, see for example, "Comprehensive Organic Chemistry", byBarton and Ollis, Pergamon Press, New York, N.Y., Vol. 4, 1979, pp.85-103 and 145-153 and references cited therein.

The pharmaceutically acceptable acid addition salts of the compounds ofthe formula (I) can be prepared by conventional procedures, e.g., byreacting the free base with the appropriate acid in an inert organicsolvent, and collecting the resulting precipitate of the salt byfiltration. If necessary, the product may then be recrystallized topurify it.

The antihypertensive activity of the compounds of the formula (I) isshown by their ability to lower the blood pressure of consciousspontaneously hypertensive rats and conscious renally hypertensive dogs,when administered orally at doses of up to 5 mg/kg.

The compounds of the invention can be administered alone, but willgenerally be administered in admixture with a pharmaceutical carrierselected with regard to the intended route of administration andstandard pharmaceutical practice. For example, they may be administeredorally in the form of tablets containing such excipients as starch orlactose, or in capsules either alone or in admixture with excipients, orin the form of elixirs or suspensions containing flavoring or coloringagents. They may be injected parenterally, for example, intramuscularly,intravenously or subcutaneously. For parenteral administration, they arebest used in the form of a sterile aqueous solution which may containother solutes, for example, enough salts or glucose to make the solutionisotonic.

Thus the invention also provides a pharmaceutical composition comprisingan antihypertensive effective amount of a compound of the formula (I) orpharmaceutically acceptable acid addition salt thereof together with apharmaceutically acceptable diluent or carrier.

The invention further provides a compound of the formula (I) or apharmaceutically acceptable acid addition salt thereof, for use intreating hypertension in mammals, including humans.

The compounds of the invention can be administered to mammals, includinghumans, for the treatment of hypertension by either the oral orparenteral routes, and may be administered orally at dosage levelsapproximately within the range 1 to 20 mg/day for an average adultpatient (70 kg) given in a single dose or up to 3 divided doses.Intravenous dosage levels would be expected to be about 1/5 to 1/10th ofthe daily oral dose. Thus for an average adult patient, individual oraldoses in tablet or capsule form will be approximately in the range from1/3 to 20 mg of the active compound. Variations will necessarilly occurdepending on the weight and condition of the subject being treated andthe particular route of administration chosen as will be known to thoseskilled in the art.

The invention yet further provides a method of treating a mammal,including a human being, having hypertension, which comprisesadministering to the mammal an antihypertensive amount of a compound ofthe formula (I) or pharmaceutically acceptable acid addition saltthereof or pharmaceutical composition as defined above.

The invention is illustrated by the following Examples, in which alltemperatures are in °C.

EXAMPLE 1 4-Amino-6,7-dimethoxy-2-[4-(4-phenylpyrimidin-2-yl)piperazino]quinazoline, hemihydrate ##STR12##

4-Amino-6,7-dimethoxy-2-piperazino-quinazoline (3.44 g, 0.012 mole) and2-chloro-4-phenylpyrimidine (2.5 g, 0.011 mole) [J. Chem. Soc., 2328(1951)] in n-butanol (250 ml) were heated under reflux for six hours.After cooling the solid product was collected, washed with diethylether,and partitioned between chloroform and saturated aqueous sodiumcarbonate solution. The chloroform layer was separated, the aqueouslayer extracted with chloroform and the combined chloroform layers werewashed with water, dried (Na₂ SO₄) and evaporated in vacuo. The residue(5 g) was chromatographed on silica eluting with chloroform andchloroform-methanol (97.5:2.5 by volume). Appropriate fractions werecombined, evaporated and the resulting solid crystallized fromdimethylformamide (DMF)/diethyl ether to give4-amino-6,7-dimethoxy-2-[4-(4-phenylpyrimidin-2-yl)-piperazino]quinazoline hemihydrate, (2.28 g), m.p. 250° C. (dec).

Analysis %: Found: C, 63.5; H, 5.8; N, 21.8. Calculated for C₂₄ H₂₅ N₇O₂.1/2H₂ O: C, 63.7; H, 5.8; N, 21.7.

The following Examples were carried out in the same general manner asExample 1, but in some cases the reaction mixture was evaporated invacuo and then purified as described. Other modifications were asfollows. In Example 4 the product from chromatography was converted tothe dihydrochloride in the standard manner, using hydrogen chloride in asuitable solvent. In Example 5, the product was collected from thecooled reaction mixture then recrystallized from ethanol. In Examples 7,8, 14 and 18, the initial reaction was carried out in ethanol and inExamples 8 and 14 the products, after chromatography, were converted tothe dihyrochloride salts. In Example 10, the product from chromatographywas further purified by preparative high pressure liquid chromatography(HPLC). In Examples 11 and 12, after basification and extraction, theresidue was recrystallized from methanol. In Example 13, the solidproduct from the reaction mixture was taken up in DMF/diethyl ether andprecipitated with water. In Example 15, the product from chromatographywas converted to the citrate salt using citric acid in a suitablesolvent, recrystallized from methanol, basified, then treated withmaleic acid, and the maleate salt recrystallized from methanol.

    __________________________________________________________________________     ##STR13##                                                                                                      Analysis %                                  Example                   Form Isolated                                                                         (calculated figures in brackets)            No.  R                    and m.p. °C.                                                                   C    H    N                                 __________________________________________________________________________          ##STR14##           Free base 202-203°                                                             57.1 (57.4                                                                         6.0 5.8                                                                            25.1 24.7)                          3                                                                                 ##STR15##           hemihydrate 191-192°                                                           61.6 (61.5                                                                         5.6 5.6                                                                            20.5 20.9)                          4                                                                                 ##STR16##           dihydrochloride 21/2 H.sub.2 O 245-248°                                        43.5 (43.2                                                                         5.1 5.8                                                                            22.3 22.4)                          5                                                                                 ##STR17##           hydrochloride 1/4 H.sub.2 O 262-264°                                           52.2 (52.2                                                                         6.2 6.2                                                                            24.4 24.3)                          6                                                                                 ##STR18##           1/3 ethanolate 225-226°                                                        59.2 (59.5                                                                         6.2 6.4                                                                            24.9 24.7)                          7                                                                                 ##STR19##           free base 227°                                                                 58.5 (58.4                                                                         6.4 6.1                                                                            23.4 23.8)                          8                                                                                 ##STR20##           dihydrochloride hydrate 265-269°                                               48.9 (48.8                                                                         5.6 6.1                                                                            19.0 19.0)                          9                                                                                 ##STR21##           free base 194-195°                                                             56.0 (56.2                                                                         5.9 5.9                                                                            23.2 22.9)                          10                                                                                ##STR22##           free base 145-150°                                                             61.9 (62.0                                                                         5.1 5.2                                                                            19.9 20.0)                          11                                                                                ##STR23##           free base 130-133°                                                             55.1 (55.5                                                                         6.7 6.7                                                                            30.8 30.8)                          12                                                                                ##STR24##           free base hydrate 276-177°                                                     48.9 (49.0                                                                         5.6 5.8                                                                            33.4 33.6)                          13                                                                                ##STR25##           hydrochloride hydrate 225-226°                                                 46.9 (47.3                                                                         5.7 5.6                                                                            23.1 23.3)                          14                                                                                ##STR26##           dihydrochloride 267-268°                                                       54.3 (54.1                                                                         5.3 5.1                                                                            18.4 18.4)                          15                                                                                ##STR27##           dimaleate hydrate 224-226°                                                     55.3 5.2 5.5                                                                            13.7 13.9)                          16                                                                                ##STR28##           free base 1/2 mole EtOAc hemihydrate 187-188.deg                              ree.    57.2 (57.0                                                                         6.7 6.7                                                                            24.2 24.2)                          17                                                                                ##STR29##           free base 263-265°                                                             59.3 (59.3                                                                         6.6 6.4                                                                            23.3 23.1)                          18                                                                                ##STR30##           free base hemihydrate 239-241°                                                 58.5 (58.1                                                                         6.4 6.5                                                                            22.8 22.6)                          19                                                                                ##STR31##           free base 238-239°                                                             54.9 (55.2                                                                         5.5  5.6                                                                           23.4 23.7)                        __________________________________________________________________________

EXAMPLE 204-Amino-6,7-dimethoxy-2-[4-(2-phenoxypyrimidin-4-yl)piperazino]quinazoline 3/4 hydrate ##STR32##

4-Amino-2-chloro-6,7-dimethoxyquinazoline (0.8 g, 3.3 mmole) and2-phenoxy-4-piperazinopyrimidine dihydrochloride (1.2 g, 3.6 mmole) wereheated under reflux in n-butanol (50 ml) overnight. The mixture was thenevaporated in vacuo and the residue partitioned betweenchloroform/methanol/saturated aqueous sodium carbonate solution (300ml:100 ml:50 ml). The chloroform/methanol layer was separated, dried(Na₂ SO₄), evaporated in vacuo then the residue (1 g) chromatographed onsilica gel (85 g). The column was eluted with chloroform, thenchloroform containing 2.5% methanol by volume, appropriate fractionscombined, evaporated in vacuo and the residue recrystallized fromethanol to give the title compound, (0.14 g) m.p. 253°-254° C.

Analysis %: Found: C, 60.8; H, 5.5; N, 20.7. Calculated for C₂₄ H₂₅ N₇O₃.3/4H₂ O: C, 60.9; H, 5.7; N, 20.7.

The following compounds were prepared by the procedure of Example 20,except that in some cases triethylamine was included in the reactionmixture and other modifications were as follows:

In Example 21, the reaction mixture was evaporated, the residuepartitioned between chloroform/water, the solid collected, boiled withmethanol, filtered and the filtrate evaporated. The residue was thenpurified by chromatography. In Example 22 the reaction mixture wasevaporated in vacuo and the residue crystallized from methanol/diethylether; in Example 24 cooling of the reaction mixture yielded4-amino-2-dimethylamino-6,7-dimethoxyquinazoline formed due toinadvertent presence of dimethylamine in the piperazino startingmaterial. The mother liquors were treated as in the general example,then the product from chromatography purified by preparative highpressure liquid chromatography and converted to the maleate salt in thestandard manner using maleic acid in a suitable solvent. In Example 27,the solid product was collected from the cooled reaction mixture and wasrecrystallized from dimethylformamide/diethyl ether. In Example 28, thesolid product was collected, recrystallized from methanol then convertedto the hydrochloride salt in the standard manner using hydrogen chloridein a suitable solvent. In Example 29 the solid product was collected andrecrystallized from dimethylformamide. In Example 30 the product fromchromatography was converted to the maleate salt using maleic acid whichsalt was crystallized from methanol. In Example 31 the solid product wascollected then washed with diethyl ether.

    __________________________________________________________________________     ##STR33##                                                                                                   Analysis %                                     Example              Form Isolated                                                                           (Theoretical in brackets)                      No.  R               and m.p., °C.                                                                    C   H   N                                      __________________________________________________________________________    21                                                                                  ##STR34##      dihydrochloride 265-266°                                                         49.0 (49.1                                                                        5.3 5.3                                                                           22.5 22.3)                               22                                                                                ##STR35##      dihydrochloride dihydrate 255-265°                                               46.2 (46.2                                                                        5.8 6.2                                                                           21.8 21.6)                               23                                                                                ##STR36##      free base 1/4 hydrate 265°                                                       54.5 (54.5                                                                        5.4 5.7                                                                           24.9 24.7)                               24                                                                                ##STR37##      dimaleate hemihydrate 203-204°                                                   51.5 (51.6                                                                        5.4 5.4                                                                           17.4 17.2)                               25                                                                                ##STR38##      free base 270-272°                                                               62.8 (62.7                                                                        5.6 5.5                                                                           21.2 21.3)                               26                                                                                ##STR39##      free base 247-248°                                                               59.1 (59.3                                                                        6.6 6.4                                                                           22.7 23.1)                               27                                                                                ##STR40##      free base 285-287°                                                               57.3 (57.4                                                                        6.0 5.8                                                                           24.9 24.7)                               28                                                                                ##STR41##      dihydrochloride 13/4 hydrate 266-268°                                            52.4 (52.6                                                                        5.5 5.6                                                                           18.3 17.9)                               29                                                                                ##STR42##      hydrochloride sesquihydrate 214-215°                                             50.6 (50.2                                                                        5.4 5.9                                                                           22.4 22.8)                               30                                                                                ##STR43##      maleate hydrate 247-248°                                                         50.6 (50.8                                                                        5.5 5.8                                                                           19.0 19.0)                               31                                                                                ##STR44##      hydrochloride 291-293°                                                           53.2 (58.5                                                                        5.6 5.5                                                                           24.5 24.3)                             __________________________________________________________________________

EXAMPLE 324-Amino-6,7-dimethoxy-2-[4-(6-hydroxypyridazin-3-yl)piperazino]quinazoline

Triethylamine (2.5 g, 0.025 mole) and4-(6-hydroxypyridazin-3-yl)piperazine hydrobromide (2.7 g, 0.011 mole)in n-butanol (150 ml) were heated to reflux, then filtered and4-amino-2-chloro-6,7-dimethoxyquinazoline (2.4 g, 0.010 mole) added tothe filtrate. The mixture was heated under reflux for three hours thenleft at room temperature for 66 hours. The solid product was collected,washed with diethyl ether, then slurried in hot methanol (50 ml),filtered and washed again with hot methanol followed by hot isopropanol.A slurry of the product in aqueous methanol (methanol:water 1:3 byvolume) was basified to pH 12 with dilute ammonium hydroxide andextracted with chloroform (100 ml) followed by chloroform-methanol(95:5; 3×100 ml). The combined organic layers were dried (Na₂ SO₄) andevaporated in vacuo to give a solid (0.6 g). The aqueous fraction wasfiltered and the solid washed with water and dried to give a further 1.6g of solid product identical when analyzed by thin layer chromatographyto the first solid. The two solids were combined then recrystallizedfrom dimethylformamide/diethyl ether and the resulting solid washed withdiethyl ether, hot isopropanol and diethyl ether again to give4-amino-6,7-dimethoxy-2-[4-(6-hydroxypyridazin-3-yl)piperazino]quinazoline (1.3 g), m.p. 296°-297° C.

Analysis %: Found: C, 55.9; H, 5.7; N, 25.2. Calculated for C₁₈ H₂₁ N₇O₃ : C, 56.4; H, 5.5; N, 25.6.

EXAMPLE 334-Amino-6,7-dimethoxy-2-[4-(6-chloropyridazin-3-yl)piperazino]quinazoline

4-Amino-6,7-dimethoxy-2-piperazinoquinazoline (3.0 g, 10.4 mmole),3-chloro-6-methoxy-pyridazine (3.96 g, 27.4 mmole) and triethylamine(5.0 g, 49.5 mmole) in n-pentanol (210 ml) were heated under reflux for25 hours. The solvent was evaporated in vacuo and the residuepartitioned between chloroform and saturated aqueous sodium carbonatesolution. The organic layer was separated, washed with water, dried (Na₂SO₄) and evaporated in vacuo. The residue was chromatographed on silicagel (200 g) eluting with chloroform followed by 5% methanol inchloroform. Further purification of the major product by HPLC using aWaters 500 Prep. LC/system, eluting with 6% by volume methanol inmethylene chloride at a flow rate of 0.15 liters per minute gave thedesired product which was recrystallized from methanol, m.p. 269°-270°C. (0.5 g).

Analysis %: Found: C, 53.7; H, 4.9; N, 24.2. Calculated for C₁₈ H₂₀ ClN₇O₂ : C, 53.8; H, 5.0; N, 24.4.

EXAMPLE 344-Amino-6,7-dimethoxy-2-[4-(2-chloropyrimidin-4-yl)piperazino]quinazoline

4-Amino-6,7-dimethoxy-2-piperazino-quinazoline (30.0 g, 0.104 mole),2,4-dichloropyrimidine (17.3 g, 0.117 mole) and triethylamine (20.5 g,0.203 mole) in ethanol (1200 ml) were heated at reflux for three hours.The solid which separated on cooling was filtered, slurried in hotisopropanol (500 ml), filtered and washed with hot methanol. The productwas partitioned between 5% by volume methanol in methylene chloride and10% (w/w) aqueous sodium carbonate solution, the organic layerseparated, washed with water, dried (Na₂ SO₄) and evaporated in vacuo.The resulting solid was slurried in hot isopropanol, filtered and washedwith hot isopropanol to afford 20 g. of the title compound, m.p. 266° C.

Analysis %: Found: C, 53.75; H, 5.0; N, 24.7. Calculated for C₁₈ H₂₀ClN₇ O₂ : C, 53.8; H, 5.0; N, 24.4.

EXAMPLE 35

Employing the above methods with the appropriate starting materials ineach case, the following compounds are obtained in like manner.

    ______________________________________                                         ##STR45##                                                                        R                                                                         ______________________________________                                        1,3,5-triazin-2-yl                                                            4-(p-Fluorophenyl)pyrimidin-2-yl                                              4-(m-Iodophenyl)pyrimidin-2-yl                                                2-(o-Methylphenyl)pyrimidin-4-yl                                              2-(p-Isopropylphenyl)pyrimidin-4-yl                                           2-(m-t-Butylphenyl)pyrimidin-4-yl                                             2-(p-t-Butoxyphenyl)pyrimidin-4-yl                                            4-(m-Ethoxyphenyl)pyrimidin-2-yl                                              4-(o-Methoxyphenyl)pyrimidin-2-yl                                             4-Phenoxypyrimidin-2-yl                                                       4-(p-Chlorophenoxy)pyrimidin-2-yl                                             4-(o-Bromophenoxy)pyrimidin-2-yl                                              2-(m-Fluorophenoxy)pyrimidin-4-yl                                             2-(p-Methylphenyl)pyrimidin-4-yl                                              2-(p-Ethylphenyl)pyrimidin-4-yl                                               4-(o-Isopropylphenyl)pyrimidin-2-yl                                           4-(o-Methoxyphenyl)pyrimidin-2-yl                                             4-n-Propylpyrimidin-2-yl                                                      6-sec-Butylpyrimidin-4-yl                                                     6-Benzylpyrimidin-4-yl                                                        4-(2-Phenylethyl)-pyrimidin-2-yl                                              4-[2-(p-Fluorophenyl)ethyl]pyrimidin-2-yl                                     4-[3-(m-Chlorophenyl)propyl]pyrimidin-2-yl                                    2-[2-(p-Methylphenyl)propyl]pyrimidin-4-yl                                    2-[3-(o-Ethoxyphenyl)propyl]pyrimidin-4-yl                                    4-[3-(p-t-Butoxyphenyl)propyl]pyrimidin-2-yl                                  4-[3-(m-n-Butylphenyl)propyl]pyrimidin-2-yl                                   4-[4-(p-Bromophenyl)butyl]pyrimidin-2-yl                                      4-[3-(p-Iodophenyl)butyl]pyrimidin-2-yl                                       2-[4-(phenylbutyl)pyrimidin-4-yl                                              4-Benzyloxypyrimidin-2-yl                                                     4-(p-Chlorophenyl)methylpyrimidin-2-yl                                        2-Ethoxypyrimidin-4-yl                                                        4-Isopropoxypyrimidin-2-yl                                                    4-n-Butoxypyrimidin-2-yl                                                      4-[2-(m-Bromophenyl)ethoxy]pyrimidin-2-yl                                     2-[1-(p-Methoxyphenyl)ethoxypyrimidin-4-yl                                    2-[3-(o-Ethylphenyl)propoxypyrimidin-4-yl                                     2-[4-(p-Fluorophenyl)butoxypyrimidin-4-yl                                     4-Methylthiopyrimidin-2-yl                                                    4-Isopropylthiopyrimidin-2-yl                                                 2-n-Butylthiopyrimidin-4-yl                                                   2-Benzylthiopyrimidin-4-yl                                                    6-(2-Phenylethylthio)pyrimidin-4-yl                                           4-[4-(p-Chlorophenyl)butylthio]  pyrimidin-2-yl                               4-[3-(m-Methoxyphenyl)propylthio]pyrimidin-2-yl                               4-Aminopyrimidin-2-yl                                                         4-Methylaminopyrimidin-2-yl                                                   4-n-Propylaminopyrimidin-2-yl                                                 6-n-Butylaminopyrimidin-4-yl                                                  6-Phenylaminopyrimidin-4-yl                                                   2-Benzylaminopyrimidin-4-yl                                                   4-(2-Phenylethyl)aminopyrimidin-2-yl                                          4-(3-p-Chlorophenylpropyl)aminopyrimidin-2-yl                                 4-N--Methyl-N--ethylaminopyrimidin-2-yl                                       6-N--Phenyl-N--propylaminopyrimidin-4-yl                                      6-N--Ethyl-N--sec-butylaminopyrimidin-4-yl                                    4-N--Methyl-N--[4-(p-chlorophenyl)butyl]pyrimidin-2-yl                        4-Cycloheptylaminopyrimidin-2-yl                                              4-Cyclohexylaminopyrimidin-2-yl                                               2-N--Cyclopropyl-N--methylpyrimidin-4-yl                                      2-N--Cyclobutyl-N--ethylpyrimidin-4-yl                                        6-N--Cyclopentyl-N--isopropylpyrimidin-4-yl                                   4-Morpholinopyrimidin-2-yl                                                    2-Thiomorpholinopyrimidin-4-yl                                                2-[1-pyrrolidinyl]pyrimidin-4-yl                                              6-Piperidinopyrimidin-4-yl                                                    6-(4-Methylpiperazino)pyrimidin-4-yl                                          6-Benzylpyridazin-3-yl                                                        6-Fluoropyridazin-3-yl                                                        6-Bromopyridazin-3-yl                                                         6-(p-Bromophenyl)pyridazin-3-yl                                               6-(o-Methylphenyl)pyridazin-3-yl                                              6-(p-t-Butoxyphenyl)pyridazin-3-yl                                            6-(m-Methoxyphenyl)pyridazin-3-yl                                             6-(p-Chlorophenoxy)pyridazin-3-yl                                             6-(p-Ethylphenoxy)pyridazin-3-yl                                              6-(p-Ethoxyphenoxy)pyridazin-3-yl                                             6-Methylpyridazin-3-yl                                                        6-Ethylpyridazin-3-yl                                                         6-Aminopyridazin-3-yl                                                         6-Methylaminopyridazin-3-yl                                                   5,6-Dimethylpyridazin-3-yl                                                    5-Amino-6-methoxypyridazin-3-yl                                               5-Amino-6-ethoxypyridazin-3-yl                                                5-Chloro-6-methoxypyridazin-3-yl                                              6-Methylaminopyridazin-4-yl                                                   6-Chloro-5-ethylpyridazin-3-yl                                                6-Chloro-5-methylpyridazin-3-yl                                               6-Amino-5-methylpyridazin-3-yl                                                4,6-Dimorpholino-1,3,5-triazin-2-yl                                           6-Ethoxy-5-methylpyrazin-2-yl                                                 6-Ethoxypyrazin-2-yl                                                          5-Ethyl-6-methoxypyrazin-2-yl                                                 5,6-Dimethylpyrazin-2-yl                                                      6-Methylpyrazin-2-yl                                                          6-n-Butylpyrazin-2-yl                                                         6-isopropylpyrazin-2-yl                                                       5-Ethoxypyrazin-2-yl                                                          5-Methoxypyrazin-2-yl                                                         5-Dimethylamino-6-methylpyrazin-2-yl                                          5-Morpholino-6-ethylpyrazin-2-yl                                              5-n-Butyl-6-Methylaminopyrazin-2-yl                                           5,6-Diethylpyrazin-2-yl                                                       5-Amino-6-methylpyrazin-2-yl                                                  5-Aminopyrazin-2-yl                                                           ______________________________________                                    

EXAMPLE 364-Amino-6,7-dimethoxy-2-[4-(2-morpholinopyrimidin-4-yl)-piperazino]quinazoline

4-Amino-6,7-dimethoxy-2-[4-(2-chloropyrimidin-4-yl)-piperazino]quinazoline (2.0 g, 5.0 mmole) and morpholine (1.1 g, 12.6 mmole) inn-butanol (150 ml) were heated in a bomb at 160° C. for 19 hours. Thesolvent was evaporated in vacuo and the residue partitioned between 5%methanol in chloroform and 5N sodium hydroxide solution. The organiclayer was separated, washed with water, dried (Na₂ SO₄) and evaporatedin vacuo. The residue was chromatographed on silica gel (20 g,"Kieselgel" (Trade Mark) 60H) eluting with chloroform. Appropriatefractions were combined and evaporated in vacuo. Crystallization fromethyl acetate gave 0.8 g of the desired product, m.p. 232°-233° C.

Analysis %: Found: C, 58.0; H, 6.3; N, 24.9. Calculated for C₂₂ H₂₈ N₈O₃ : C, 58.4; H, 6.2; N, 24.8.

EXAMPLE 37

4-Amino-6,7-dimethoxy-2-[4-(2-{N-cyclopentyl-N-methylamino}pyrimidin-4-yl)piperazino]quinazoline was prepared in a manner similar to that of Example 36,starting from the product of Example 34 and N-cyclopentylmethylamine,but a temperature of 180° for 48 hours was required. The product wascharacterized as the dihydrochloride dihydrate, m.p. 333°-4° C.

Analysis %: Found: C, 50.0; H, 6.2; N, 19.8. Calculated for C₂₄ H₃₂ N₈O₂.2HCl.2H₂ O: C, 50.3; H, 6.7; N, 19.5.

EXAMPLE 38

4-Amino-6,7-dimethoxy-2-[4-(2-N-methylanilinopyrimidin-4-yl)piperazino]quinazoline, m.p. 252°-3° C., was prepared in a manner similar toExample 36, starting from the product of Example 34 and N-methylaniline.

Analysis %: Found: C, 63.4; H, 6.0; N, 23.8. Calculated for C₂₅ H₂₈ N₈O₂ : C, 63.5; H, 6.0; N, 23.7.

EXAMPLE 39

In like manner the following products are prepared by the method ofExamples 36-38 as outlined below ##STR46## where X is Cl or Br and R⁴and R⁵ are as defined below.

    ______________________________________                                        R.sup.4            R.sup.5                                                    ______________________________________                                        H                  CH.sub.3                                                   H                  C.sub.2 H.sub.5                                            H                  CH(CH.sub.3).sub.2                                         H                  (CH.sub.2).sub.3 CH.sub.3                                  H                  CH.sub.2 CH(CH.sub.3).sub.2                                H                  C.sub.6 H.sub.5                                            H                  cyclopropyl                                                H                  cyclopentyl                                                H                  cyclohexyl                                                 H                  cycloheptyl                                                CH.sub.3           C.sub.2 H.sub.5                                            C.sub.2 H.sub.5    C.sub.2 H.sub.5                                            n-C.sub.3 H.sub.7  C.sub.2 H.sub.5                                            n-C.sub.3 H.sub.7  n-C.sub.4 H.sub.9                                          n-C.sub.4 H.sub.9  n-C.sub.4 H.sub.9                                          CH.sub.3           cyclopropyl                                                C.sub.2 H.sub.5    cyclobutyl                                                 n-C.sub.3 H.sub.7  cyclopentyl                                                CH.sub.3           cyclohexyl                                                 H                  benzyl                                                     H                  2-phenylethyl                                              CH.sub.3           3-phenylpropyl                                             C.sub.2 H.sub.5    3-phenylbutyl                                              ______________________________________                                    

or R⁴ +R⁵ +N is:

thiomorpholin,

piperidino

4-methylpiperazino

EXAMPLE 40

By employing a compound of formula (I) where R is4-halo-1,3,5-triazin-2-yl or 4,6-dihalo-1,3,5-triazin-2-yl, thefollowing compounds are obtained by the methods of Examples 36-38, wherehalo is Cl or Br. ##STR47## where R¹ is hydrogen or NR⁴ R⁵ and R² is NR⁴R⁵ where R⁴ and R⁵ are as defined in Example 39.

EXAMPLE 41

To a solution of 2.0 mmole4-amino-6,7-dimethoxy-2-[4-(2-chloropyrimidin-4-yl)-piperazino]quinazoline in n-butanol is added 20 ml of 0.1N hydrogen chloride inbutanol. The resulting mixture is stirred for a few minutes, the solventevaporated in vacuo to a small volume and the residue treated with ethylether to complete the precipitation of the hydrochloride salt.

In similar manner the remaining compounds of formula (I) are convertedto hydrochloride salts.

When the hydrogen chloride employed above is replaced by one of thefollowing acids the corresponding salts are obtained in like manner:

hydrogen bromide, hydrogen iodine, sulfuric acid, ammonium bisulfate,phosphoric acid, potassium dihydrogen phosphate, acetic acid, maleicacid, fumaric acid, succinic acid, lactic acid, tartaric acid, citricacid, gluconic acid, saccharic acid, methylsulfonic acid andp-toluenesulfonic acid.

PREPARATION A 2-Phenoxy-4-piperazinopyrimidine

i. 2-Chloro-4-(4-formylpiperazino)pyrimidine

1-Formylpiperazine (38.5 g) and triethylamine (34 g) in ethanol (500 ml)were added slowly to a stirred solution of 2,4-dichloropyrimidine (50 g)in ethanol (2.5 ml) at room temperature. The mixture was stirred at roomtemperature for 24 hours then evaporated in vacuo and the residuepartitioned between chloroform and water. The organic phase was washedwith water and the combined aqueous phases extracted with chloroform.The combined chloroform extracts were dried (Na₂ SO₄), evaporated invacuo and the residue was crystallized twice from ethyl acetate to give2-chloro-4-(4-formylpiperazino)pyrimidine, (24 g), m.p. 125°-126° C.

Analysis %: Found: C, 47.5; H, 4.8; N, 24.4. Calculated for C₉ H₁₁ ClN₄O: C, 47.7; H, 4.9; N, 24.7.

A further 6.0 g of product was obtained on evaporation of the ethylacetate to half volume and cooling.

ii. 2-Phenoxy-4-(4-formylpiperazino)pyrimidine 1/4 hydrate

Phenol (2.07 g) was added to a solution of sodium methoxide (from 0.51 gsodium) in dry methanol (20 ml) then the solvent was evaporated invacuo. The sodium phenoxide residue in 1,2-dimethoxyethane (160 ml) wastreated with 2-chloro-4-(4-formylpiperazino)pyrimidine (5.0 g) andheated under reflux for 24 hours. The solvent was evaporated in vacuoand the residue partitioned between chloroform (50 ml) and water (30ml). The aqueous layer was extracted with chloroform and the combinedchloroform extracts were dried (Na₂ SO₄) and evaporated in vacuo. Theresidue was triturated with diethyl ether and the resulting solidre-crystallized from ethyl acetate to give2-phenoxy-4-(4-formylpiperazino)pyrimidine 1/4 hydrate (2.93 g) m.p.149°-151° C.

Analysis %: Found: C,62.0; H,5.8; N,19.7. Calculated for C₁₅ H₁₆ N₄O₂.1/4H₂ O: C,62.4; H,5.8; N,19.4.

iii. 2-Phenoxy-4-piperazinopyrimidine

2-Phenoxy-4-(4-formylpiperazino)pyrimidine (2.6 g) in methanol (27 ml)and 2N hydrochloric acid (6.9 ml) was left at room temperature for 24hours and then heated on a steam bath for 30 minutes. The solvent wasevaporated in vacuo and the residue re-crystallized twice fromisopropanol to give 2-phenoxy-4-piperazinopyrimidine (1.5 g)characterized spectroscopically, and used directly.

PREPARATION B 2-dimethylamino-4-piperazinopyrimidine, dihydrochloride3/4 hydrate ##STR48##

i. 2-Chloro-4-(4-formylpiperazino)pyrimidine (5.0 g) and dimethylamine(7.8 ml, 33% solution in ethanol) in ethanol (70 ml) were heated underreflux for 8 hours. The solvent was evaporated in vacuo and the residuewas partitioned between chloroform and water. The aqueous layer wasextracted twice with chloroform and the combined chloroform layers dried(Na₂ SO₄) and evaporated in vacuo. The residue was re-crystallized fromethyl acetate to give 2-dimethylamino-4-(4-formylpiperazino)pyrimidine(2.7 g), m.p. 116° C.

Analysis %: Found: C,55.9; H,7.2; N,29.5. Calculated for C₁₁ H₁₇ N₅ O:C,56.1; H,7.3; N,29.8

ii. This product (2.5 g) in methanol (31 ml) and 2N hydrochloric acid (8ml) was stirred at room temperature for 2.25 hours and then heated on asteam bath for 2.25 hours. The solvent was evaporated in vacuo and theresidue crystallized from ethanol to give2-dimethyl-amino-4-piperazinopyrimidine, dihydrochloride, 3/4 hydratem.p. 260°-270° C.

Analysis %: Found: C, 41.0; H, 6.9; N, 24.0. Calculated for C₁₀ H₁₇N₅.2HCl.3/4H₂ O: C, 40.9; H, 7.0; N, 23.9.

PREPARATION C 2-Hydroxy-4-piperazinopyrimidine, dihydrochloride

2-Chloro-4-(4-formylpiperazino)pyrimidine (5.0 g) in 2N hydrochloricacid (17 ml) was stirred at room temperature for 2.25 hours and thenheated on a steam bath for 2.25 hours. The solvent was evaporated invacuo and replaced by 6N hydrochloric acid (30 ml). The solution washeated on a steam bath for 2.5 hours and then evaporated in vacuo.T.L.C. indicated reaction was still incomplete and therefore the residuein concentrated hydrochloric acid (30 ml) was heated on a steam bath for3 hours and then evaporated in vacuo. The residue crystallized frommethanol to give 2-hydroxy-4-piperazinopyrimidine, dihydrochloride (2.3g), m.p.>250° C.

Analysis %: Found: C, 37.6; H, 5.7; N, 21.9. Calculated for C₈ H₁₂ N₄O.2HCl: C, 38.0; H, 5.6; N, 22.1.

PREPARATION D 4-Chloro-6-isopropoxy-pyrimidine ##STR49##

A solution of sodium isopropoxide (prepared from 0.77 g sodium) inisopropanol (230 ml) was added dropwise over 8 hours to a stirredsolution of 4,6-dichloropyrimidine (5.0 g) in isopropanol (60 ml) atroom temperature. The solvent was evaporated in vacuo, the residue takenup in water and extracted three times with diethylether (3×70 ml). Thecombined ether extracts were dried (Na₂ SO₄) and evaporated in vacuo togive 4-chloro-6-isopropoxy pyrimidine (4.4 g) as an oil, characterizedspectroscopically, and used directly.

PREPARATION E 3-Isopropoxy-6-piperazinopyridazine ##STR50##

3-Chloro-6-piperazinopyridazine (4.0 g) [J. Med. Chem., 5, 541 (1963)]and sodium isopropoxide, prepared by addition of sodium (0.7 g) to dryisopropanol (70 ml), were heated in a bomb at 130°-140° C. for 10 hours.The solvent was evaporated in vacuo, the residue taken up in methylenechloride (300 ml) and the resulting solution washed with water (2×50ml). The organic extract was dried (Na₂ SO₄) and evaporated in vacuo togive 3-isopropoxy-6-piperazinopyridazine (3.3 g). A sample in ethylacetate, was converted to the maleate salt by treatment with maleic acidin ethyl acetate. The resulting solid was re-crystallized from ethanol,m.p. 144°-145° C.

Analysis: Found: C,49.1; H,5.7; N,11.7 Calculated for C₁₁ H₁₈ N₄ O.2C₄H₄ O₄.1/2H₂ O: C,49.2; H,5.9; N, 12.1.

PREPARATION F Preparation of 4-(6-hydroxypyridazin-3-yl)piperazine,hydrobromide ##STR51##

4-(6-Methoxypyridazin-3-yl)piperazine (7.2 g) (J. Med. Chem. 1963, 5,541) in 48% hydrobromic acid (140 ml) was heated at 110°-120° for 11/2hours, left at room temperature overnight, then heated at 120° for afurther 1 hour. The solvent was evaporated in vacuo and the residuetreated twice with isopropanol and evaporated to dryness. The resultingsolid was triturated with diethyl ether, filtered and washed with etherto give 4-(6-hydroxypyridazin-3-yl)piperazine, hydrobromide (11.2 g). Asample re-crystallized from ethanol had m.p. 289°-291°.

Analysis %: Found: C,36.8; H,5.0; N,21.4 Calculated for C₈ H₁₂ N₄ O.HBr:C,36.8; H,5.0; N,21.5.

PREPARATION G Preparation of 4,6-diethoxy-2-piperazino-1,3,5-triazine##STR52##

(a) 4,6-Dichloro-2-(4-formylpiperazino)-1,3,5-triazine

1-Formylpiperazine (5.0 g) in dry acetone (28 ml) was added dropwise toa stirred suspension of cyanuric chloride (6.2 g) and sodium bicarbonate(2.58 g) in dry acetone (153 ml) at -35°. The reaction mixture wasstirred at -30° for 13/4 hours. Insoluble material was removed byfiltration and washed with acetone. The combined filtrate and washingswere evaporated in vacuo and the residue taken up in methylene chloride,filtered and the filtrate evaporated in vacuo. The resulting solid wasre-crystallized twice from ethyl acetate to give in two fractions4,6-dichloro-2-(4-formylpiperazino)1,3,5-triazine (3.1 g) m.p.163°-165°.

Analysis %: Found: C,36.5; H,3.4; N,27.1. Calculated for C₈ H₉ Cl₂ N₅ O:C,36.7; H,3.5; N,26.7.

(b) 4,6-diethoxy-2-(4-formylpiperazino)-1,3,5 triazine

A solution of sodium ethoxide in dry ethanol (prepared from 1.76 gsodium in 100 ml ethanol) was added dropwise to a stirred suspension of2,4-dichloro-6-(4-formylpiperazino)-1,3,5-triazine (10 g) in dry ethanol(740 ml). The reaction mixture was stirred at room temperature for 6hours. The solvent was evaporated in vacuo and the residue partitionedbetween methylene chloride and water. The organic layer was separated,washed 3 times with water, dried (Na₂ SO₄) and evaporated in vacuo togive a solid (7.2 g). Re-crystallization from ethyl acetate gave4,6-diethoxy-2-(4-formylpiperazino)-1,3,5-triazine (6.6 g), m.p.106°-108.5°.

Analysis %: Found: C,51.3; H,6.8; N,24.7. Calculated for C₁₂ H₁₉ N₅ O₃ :C,51.2; H,6.8; N,24.9.

(c) 4,6-Diethoxy-2-piperazino-1,3,5-triazine

The product from (b) (3.25 g) in potassium hydroxide solution (1N, 20ml) and ethanol (30 ml) was left at room temperature for 3 hours. Thenfurther potassium hydroxide solution (20 ml) was added. After 45 minutesthe reaction mixture was extracted with chloroform (5×30 ml), and thecombined chloroform extracts dried (Na₂ SO₄) and evaporated in vacuo togive 4,6-diethoxy-2-piperazino-1,3,5-triazine (3.0 g) as an oil. Theproduct was characterized spectroscopically and used directly withoutfurther purification.

PREPARATION H Preparation of 3-Phenoxy-6-piperazinopyridazine ##STR53##

Phenol (39.8 g) was treated with a solution of sodium methoxide inmethanol (prepared from 0.7 g sodium in 60 ml dry methanol) and thesolvent evaporated in vacuo. 3-Chloro-6-piperazinopyridazine (4.0 g) wasadded to the resulting mixture of sodium phenate and phenol and themixture heated at 125°-130° for 10 hours with stirring. Methylenechloride (200 ml) was added to the cooled reaction mixture and thesolution was washed with aqueous sodium hydroxide solution (3×60 ml,10%). The organic layer was dried (Na₂ SO₄) and evaporated in vacuo. Theresidue was taken up in isopropanol, treated with charcoal, filteredthrough "Hyflo" and evaporated in vacuo. Chromatography of the residueon silica ("Keiselgel H", 15 g) eluting with chloroform gave3-phenoxy-6-piperazinopyridazine (2.0 g). A sample re-crystallized fromethyl acetate as the hemihydrate, m.p. 96°-97°.

Analysis %: Found: C,63.1; H,6.2; N,21.4. Calculated for C₁₄ H₁₆ N₄O.1/2H₂ O: C,63.4; H,6.5; N,21.1.

PREPARATION I Preparation of4-chloro-6-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl)pyrimidine

Sodium hydroxide solution (80 ml, IN) was added to a suspension of6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride in water (20ml) followed by 4,6-dichloropyrimidine (5.95 g) and the mixture washeated on a steam bath for 5 hours. The solvent was evaporated in vacuoto give a brown oil which solidified on standing. Re-crystallizationfrom aqueous ethanol followed by isopropanol gave4-chloro-6-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinol-2-yl)pyrimidine(6.0 g). An analytical sample re-crystallized from isopropanol, m.p.88°-89°.

We claim:
 1. A compound of the formula ##STR54## or a pharmaceuticallyacceptable acid addition salt thereof, wherein R is of the formula##STR55## wherein R¹ is hydrogen and R² is6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl, or R¹ and R² are eacha member selected from the group consisting of hydrogen, hydroxy, F, Cl,Br, I, (alk)R³, O(alk)R³, S(alk)R³, NR⁴ R⁵, C₆ H₄ R⁶ and OC₆ H₄ R⁶,where (alk) is (C₁ -C₄)alkylene, R³ is hydrogen or C₆ H₄ R⁶, when takenseparately, R⁴ is hydrogen or (C₁ -C₄)alkyl and R⁵ is hydrogen, phenyl,(alk)R³ or (C₃ -C₇)cycloalkyl, or R⁴ and R⁵ taken together with thenitrogen atom to which they are attached form a pyrrolo, piperidino,4-methyl-piperazino, morpholino or thiomorpholino group and R⁶ ishydrogen, F, Cl, Br, I, (C₁ -C₄)alkyl or (C₁ -C₄)alkoxy.
 2. A compoundaccording to claim 1 wherein R is ##STR56##
 3. A compound according toclaim 2 wherein R² is hydrogen, hydroxy, F, Cl, Br, (alk)R³, O(alk)R³,NR⁴ R⁵, C₆ H₄ R⁶ or OC₆ H₄ R⁶.
 4. A compound according to claim 3wherein R² is hydrogen, hydroxy, Cl, N(CH₃)₂, OC₆ H₅, OCH₃, OCH(CH₃)₂ orC₆ H₅.
 5. A compound according to claim 4 wherein R² is hydrogen orOCH(CH₃)₂.
 6. The compound according to claim 5 wherein R² is hydrogen.7. The compound according to claim 5 wherein R² is OCH(CH₃)₂.
 8. Amethod for treating mammalian hypertension which comprises orally orparenterally administering to a mammal in need of such treatment anantihypertensive effective amount of a compound according to claim
 1. 9.A pharmaceutical composition for oral or parenteral administration to amammal comprising a pharmaceutically acceptable carrier and anantihypertensive effective amount of a compound according to claim 1.